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Presentation on theme: "Drugs used in the treatment of hyperlipidemias"— Presentation transcript:

2 Introduction Introduction CholesterolUsed to prevent or slow progression of atherosclerosis to reduce the risk of coronary artery disease and prolong lifeCholesterolAdvantagesServes as a component of cell membranes and intracellular organelle membranesIs involved in the synthesis of certain hormones including estrogen, progesterone, testosterone, adrenal corticosteroidsNeeded for the synthesis of bile salts which are needed for digestion and absorption of fats.

3 Introduction Cholesterol Advantages OriginIs deposited in the stratum corneum of the skin to help ↓ evaporation of water and create impermeability to water soluble compounds (helps keep moisture in skin)OriginIs synthesized in the liver. Acetyl CoA is converted to mevalonic acid and ultimately to cholesterol by hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase.

4 Introduction Cholesterol OriginEndogenous synthesis of cholesterol increases at nightAn increase in dietary cholesterol produces only a small ↑ in blood levels of cholesterol because ingestion inhibits endogenous synthesisDietary saturated fats ↑ blood cholesterol levels because they are converted to cholesterol in the body.

5 Introduction LipoproteinsServe as carriers for transporting lipids (cholesterol and triglycerides) in the blood.ApolipoproteinsEmbedded in the lipoprotein shellThree functions1. Serve as recognition sites for cell-surface receptors; allowing cells to bind and ingest the lipoprotein.2. Activate enzymes that will metabolize the lipoprotein3. ↑ structural stability of the lipoprotein

7 Introduction Lipoproteins Lipoproteins of importanceVLDL (very low density lipoprotein)Contain triglycerides (TGs) and some cholesterolAccount for nearly all TGs in the bloodContain B-100Deliver triglycerides from the liver to adipose tissues and muscles.

8 Introduction Lipoproteins Lipoproteins of importanceVLDL (very low density lipoprotein)Remnants of hydrolysis are IDL (intermediate density lipoproteins), which can be transported to liver or converted to LDL

13 The major pathways involved in the metabolism of chylomicrons synthesized by the intestine and VLDL synthesized by the liverMetabolism of lipoproteins of hepatic origin. The heavy arrows show the primary pathways. Nascent VLDL are secreted via the Golgi apparatus. They acquire additional apoC lipoproteins and apolipoprotein E (apoE) from HDL. Very-low-density lipoproteins (VLDL) are converted to VLDL remnants (IDL) by lipolysis via lipoprotein lipase in the vessels of peripheral tissues. In the process, C apolipoproteins and a portion of the apoE are given back to high-density lipoproteins (HDL). Some of the VLDL remnants are converted to LDL by further loss of triglycerides and loss of apoE. A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver and the peripheral tissues, for which apo B-100 is the ligand. Dark color denotes cholesteryl esters; light color denotes triglycerides; the asterisk denotes a functional ligand for LDL receptors; triangles indicate apoE; circles and squares represent C apolipoproteins. FFA, free fatty acid; RER, rough endoplasmic reticulum.(Modified and redrawn, with permission, from Kane J, Malloy M: Disorders of lipoproteins. In: Rosenberg RN et al [editors]: The Molecular and Genetic Basis of Neurological Disease. Butterworth-Heinemann, 1993.)

21 Antilipemic agents Niacin IndicationsDrug of choice for ↓ levels of TG (VLDL) in pts at risk for pancreatitisMixed elevation of LDL and VLDL (alone or in combination with reductase inh.)Elevation of TG (VLDL) and low levels of HDL (Niaspan® - approved for elevating HDL levels)Start with low dose and gradually increaseGiven 1-3g/day in divided doses or once daily with extended release. Give at night with food.

22 Antilipemic agents Niacin - Adverse effects FlushingHarmless cutaneous vasodilationUncomfortable sensation of warmthOccurs after drug is started or ↑ doseLasts for the first several weeksCan give 325mg aspirin 30 minutes before each dose (prevents prostaglandin synthesis). Can also take ibuprofen QD in place of ASA

27 Hepatic and peripheral effects of fibratesHepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-, which modulates the expression of several proteins. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins

34 Antilipemic agentsBile Acid-Binding Resins (colestipol and cholestyramine)Will ↓ LDL, may ↑ VLDL (would require niacin combo if ↑ TG prior to tx)MOABile acids, the metabolites of cholesterol, are normally reabsorbed in the jejunum and ileum. When resins are given, they bind to bile acids in the intestinal lumen, prevent their reabsorption and increase their excretion.

36 Antilipemic agents Bile Acid-Binding Resins Indication Adverse EffectsCan be used to relieve pruitis in pts who have cholestasisCan be used for severe digitalis toxicityDispensed in powder form (must be mixed with fluid). Cholestyramine 4-12g BID. Colestipol 5-30g/day in divided doses and also in 1g tablets (2-16g/day) taken w/ fluidAdverse EffectsMax reductions of LDL occur in one monthMust be taken with meals

40 Inhibition of HMG-CoA reductaseInhibition of HMG-CoA reductase. Top: The HMG-CoA intermediate that is the immediate precursor of mevalonate, a critical compound in the synthesis of cholesterol. Bottom: The structure of lovastatin and its active form, showing the similarity to the normal HMG-CoA intermediate (shaded areas).

41 Antilipemic agents (“statins”) MOA Inhibits hepatic HMG CoA reductaseInhibition of cholesterol synthesis causes hepatocytes to synthesize more LDL receptorsHepatocytes are able to remove more LDLs from the bloodDecrease production of apolipoprotein B-100, thereby ↓ production of VLDL↓ plaque cholesterol content

42 Antilipemic agents (“statins”) MOA ↓ inflammation at the plaque siteImprove abnormal endothelial functionEnhance the ability of blood vessels to dilate↓ risk of thrombosis (inhibits platelet aggregation and blocks thrombin synthesis)Statins have high first pass extraction by liver (only a small fraction of each dose reaches the general circulation)Prodrugs – lovastatin and simvastatin

43 Antilipemic agents (“statins”) – Indications Used alone to ↓ LDLUsed with bile acid – binding resins to ↓ LDLUsed with niacin to ↓ LDL, ↓ VLDL, and ↑ HDLEnhanced if taken with food (except for pravastatin – taken without food)Give in the eveningHalf life is 1-3 hours (except atorvastatin – 14 hours)

49 Antilipemic agents Ezetimibeezetimibe reduced cholesterol absorption by 54%Cholesterol lowering agentWill challenge the statinsApproved for monotherapy or in combo with statinsreduction of 60% with simvastatin for LDL-C